Synthesis of l-[4-¹¹C]Asparagine by Ring-Opening Nucleophilic ¹¹C-Cyanation Reaction of a Chiral Cyclic Sulfamidate Precursor

The development of a convenient and rapid method to synthesize radiolabeled, enantiomerically pure amino acids (AAs) as potential positron emission tomography (PET) imaging agents for mapping various biochemical transformations in living organisms remains a challenge. This is especially true for the synthesis of carbon-11-labeled AAs given the short half-life of carbon-11 (¹¹C, t_1/2=20.4 min). A facile synthetic pathway to prepare enantiomerically pure ¹¹C-labeled l-asparagine was developed using a partially protected serine as a starting material with a four-step transformation providing a chiral five-membered cyclic sulfamidate as the radiolabeling precursor. Its structure and absolute configuration were confirmed by X-ray crystallography. Utilizing a [¹¹C]cyanide nucleophilic ring opening reaction followed by selective acidic hydrolysis and deprotection, enantiomerically pure l-[4-¹¹C]asparagine was synthesized. Further optimization of reaction parameters, including base, metal ion source, solvent, acid component, reaction temperature and reaction time, a reliable two-step method for synthesizing l-[4-¹¹C]asparagine was presented: within a 45±3 min (n=5, from end-of-bombardment), the desired enantiomerically pure product was synthesized with the initial nucleophilic cyanation yield of 69±4 % (n=5) and overall two-step radiochemical yield of 53±2 % (n=5) based on starting [¹¹C]HCN, and with radiochemical purity of 96±2 % (n=5).